BACKGROUND/AIMS: Bosentan, a dual endothelin ET(A/B) receptor antagonist, may cause dose-dependent reversible cholestatic liver injury. We herein tested whether bosentan or metabolites, both eliminated in bile, induce alterations in bile secretion. METHODS: Bile flow and output of bile constituents were monitored in pentobarbital-anesthetized rats with biliary fistulas. Normal and TR(-) rats with a genetic defect in mrp2, received bosentan intravenous injections. RESULTS: Bosentan bolus intravenous injections of 0.1-10mg/kg triggered a dose-dependent increase in biliary bilirubin excretion. In addition, doses (> or =10mg/kg) caused a sustained increase in canalicular bile salt-independent bile flow, combined with significant increases in the concentration and output of glutathione and of bicarbonate in bile. In rats receiving bosentan (> or =10mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2micromol/min/kg), phospholipid and cholesterol secretions were profoundly inhibited and uncoupled from bile salt secretion. In TR(-) rats, the choleretic effect of bosentan was reduced to non-significant levels. The stimulation of bilirubin secretion and the uncoupling of phospholipid from bile salt secretion were absent, whereas that of cholesterol was maintained. CONCLUSIONS: Bosentan alters canalicular bile formation in major part via mrp2-mediated mechanisms. Intermittent uncoupling of lipid from bile salt secretion may contribute to bosentan hepatic adverse reaction.
BACKGROUND/AIMS: Bosentan, a dual endothelin ET(A/B) receptor antagonist, may cause dose-dependent reversible cholestatic liver injury. We herein tested whether bosentan or metabolites, both eliminated in bile, induce alterations in bile secretion. METHODS: Bile flow and output of bile constituents were monitored in pentobarbital-anesthetized rats with biliary fistulas. Normal and TR(-) rats with a genetic defect in mrp2, received bosentan intravenous injections. RESULTS:Bosentan bolus intravenous injections of 0.1-10mg/kg triggered a dose-dependent increase in biliary bilirubin excretion. In addition, doses (> or =10mg/kg) caused a sustained increase in canalicular bile salt-independent bile flow, combined with significant increases in the concentration and output of glutathione and of bicarbonate in bile. In rats receiving bosentan (> or =10mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2micromol/min/kg), phospholipid and cholesterol secretions were profoundly inhibited and uncoupled from bile salt secretion. In TR(-) rats, the choleretic effect of bosentan was reduced to non-significant levels. The stimulation of bilirubin secretion and the uncoupling of phospholipid from bile salt secretion were absent, whereas that of cholesterol was maintained. CONCLUSIONS:Bosentan alters canalicular bile formation in major part via mrp2-mediated mechanisms. Intermittent uncoupling of lipid from bile salt secretion may contribute to bosentanhepatic adverse reaction.
Authors: C Fahrmayr; J König; D Auge; M Mieth; K Münch; J Segrestaa; T Pfeifer; A Treiber; Mf Fromm Journal: Br J Pharmacol Date: 2013-05 Impact factor: 8.739
Authors: Dan Xu; Manhong Wu; Sachiko Nishimura; Toshihiko Nishimura; Sara A Michie; Ming Zheng; Zicheng Yang; Alexander John Yates; Jeffrey S Day; Kathleen M Hillgren; Saori Takedai Takeda; Yuan Guan; Yingying Guo; Gary Peltz Journal: J Pharmacol Exp Ther Date: 2014-11-25 Impact factor: 4.030
Authors: S M Markova; T De Marco; N Bendjilali; E A Kobashigawa; J Mefford; J Sodhi; H Le; C Zhang; J Halladay; A E Rettie; C Khojasteh; D McGlothlin; A H B Wu; W-C Hsueh; J S Witte; J B Schwartz; D L Kroetz Journal: Clin Pharmacol Ther Date: 2013-07-17 Impact factor: 6.875